tbuckley/cabot-search huggingface dataset:
Sixty seconds on . . . the woman who can smell Parkinson’s
Authors: Gareth Iacobucci
Journal: BMJ (2022)

Obesity is a growing epidemic within the USA. Because weight gain is associated with an increased risk of developing life-threatening comorbidities, such as hypertension or type 2 diabetes, there is great interest in developing non-invasive pharmacotherapeutics to help combat obesity. Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of antidiabetic medications that have shown promise in encouraging glycemic control and promoting weight loss in patients with or without type 2 diabetes. This literature review summarizes and discusses the weight loss results from the SUSTAIN (Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes), PIONEER (Peptide Innovation for Early Diabetes Treatment), and STEP (Semaglutide Treatment Effect in People with Obesity) clinical trial programs. The SUSTAIN and PIONEER clinical trials studied the use of 1.0 mg, once-weekly, subcutaneous and oral semaglutide (a new GLP-1 homolog), respectively, on participants with type 2 diabetes. The STEP trial examined the effects of 2.4 mg, once-weekly, subcutaneous semaglutide on patients with obesity. Trial data and other pertinent articles were obtained via database search through the US National Library of Medicine Clinical Trials and the National Center for Biotechnology Information. All three clinical trials demonstrated that semaglutide (injected or oral) has superior efficacy compared with placebo and other antidiabetic medications in weight reduction, which led to Food and Drug Administration approval of Wegovy (semaglutide) for weight loss.
Antiretroviral Therapy for HIV Infection in 1996
Authors: Charles C. J. Carpenter
Journal: JAMA (1996)

<h3>Objective.</h3> —To provide clinical recommendations for antiretroviral therapy for human immunodeficiency virus (HIV) disease with currently (mid 1996) available drugs. When to start therapy, what to start with, when to change, and what to change to were addressed. <h3>Participants.</h3> —A 13-member panel representing international expertise in antiretroviral research and HIV patient care was selected by the International AIDS Society—USA. <h3>Evidence.</h3> —Available clinical and basic science data, including phase 3 controlled trials, clinical endpoint data, virologic and immunologic endpoint data, interim analyses, studies of HIV pathophysiology, and expert opinions of panel members were considered. Recommendations were limited to drugs available in mid 1996. <h3>Process.</h3> —For each question posed, 1 or more member(s) reviewed and presented available data. Recommendations were determined by group consensus (January 1996); revisions as warranted by new data were incorporated by group consensus (February-May 1996). <h3>Conclusions.</h3> —Recent data on HIV pathogenesis, methods to determine plasma HIV RNA, clinical trial data, and availability of new drugs point to the need for new approaches to treatment. Therapy is recommended based on CD4<sup>+</sup>cell count, plasma HIV RNA level, or clinical status. Preferred initial drug regimens include nucleoside combinations; at present protease inhibitors are probably best reserved for patients at higher progression risk. For treatment failure or drug intolerance, subsequent regimen considerations include reasons for changing therapy, available drug options, disease stage, underlying conditions, and concomitant medication(s). Therapy for primary (acute) infection, high-risk exposures to HIV, and maternal-to-fetal transmission are also addressed. Therapeutic approaches need to be updated as new data continue to emerge.
Abstract 3770: Concentration-dependent Divergent Hypertrophic Effects of Estrogen in Adult Ventricular Myocytes
Authors: Ana Kilic, Sabzali A Javadov, Morris Karmazyn
Journal: Circulation (2008)

High concentrations of estrogen have been shown to attenuate myocardial hypertrophy and left ventricular remodeling. However, the effects of low concentration of estrogen observed in postmenopausal women on cardiac hypertrophy have not been studied. In the present study we examined the effects of high (0.1 and 1 nM) and low (1 and 10 pM) concentration of the synthetic analog of estradiol, 17β-estradiol (E2) on adult cardiomyocytes (CMs). CMs were isolated from adult male and female Sprague-Dawley rats. The cells were used immediately after isolation to measure pH i or cultured to assess hypertrophic phenotype (cell surface area), gene markers (atrial natriuretic peptide, ANP), and protein activation. Low concentration of E2 (1 and 10 pM) increased cell surface area (females: 20%, P &lt;0.05; males: 28%, P &lt;0.05) and ANP expression (females: 394%, P &lt;0.05; males: 497%, P &lt;0.05) after 24 h. However, high concentrations (0.1 and 1 nM) of E2 did not induce cell hypertrophy but instead blocked the hypertrophic effect of the α 1 -agonist phenylephrinerophy. The pro-hypertrophic effect of low concentration of E2 was prevented by the sodium-hydrogen exchange isoform 1 (NHE-1) specific inhibitor AVE-4890 (AVE, 5 μM) suggesting involvement of NHE-1 in mediating the E2-induced hypertrophy. Fluorometric measurements with the pH i -sensitive dye BCECF demonstrated that a 1 pM E2 increased the pH i (females: +0.05 pH units; males +0.12 pH units, P &lt;0.05) by a rapid non-genomic mechanism that was blocked by AVE. On the other hand, 1 nM E2 decreased the pH i (females: −0.24 pH units, P &lt;0.05; males: −0.07 pH units, P &lt;0.05) and this effect was also prevented by AVE. The NHE-1-mediated pro-hypertrophic effect of 1 pM E2 was dependent on phosphorylation of ERK1/2 MAPK since the effect was blocked with the ERK1/2 inhibitor PD98059 (10 μM) and there was no gender difference on ERK1/2 activation. E2 has a dual concentration-dependent role in adult CMs as manifested by a pro-hypertrophic effect at low concentrations (1 and 10 pM), and conversely, an anti-hypertrophic effect at high concentrations (0.1 and 1 nM). The pro-hypertrophic effect of E2 is mediated, at least in part, through ERK1/2/NHE-1 activation.
Comparative study of cathepsin B-cleavable linkers for the optimal design of cathepsin B-specific doxorubicin prodrug nanoparticles for targeted cancer therapy
Authors: Nayeon Shim, Seong Ik Jeon, Suah Yang, Jung Yeon Park, Mihee Jo, Jinseong Kim, Jiwoong Choi, Wan Su Yun, Jeongrae Kim, Youngjoo Lee, Man Kyu Shim, Yongju Kim, Kwangmeyung Kim
Journal: Biomaterials (2022)
Abstract IA030: A population-based, whole genome sequencing approach to mapping the genetic basis of mesenchymal malignancies
Authors: David M. Thomas
Journal: Clinical Cancer Research (2022)

Abstract Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify novel pathways specific to mesenchymal cancers, whole genome germline sequencing was performed on 1,644 sporadic cases, and 3,205 matched healthy elderly controls. Using an extreme phenotype design, a combined rare variant burden and ontologic analysis identified two new sarcoma-specific pathways involved in mitotic and telomere functions. Variants in centrosome genes are linked to malignant peripheral nerve sheath and gastrointestinal stromal tumors, while heritable defects in the shelterin complex link susceptibility to sarcoma, melanoma and thyroid cancers. These studies indicate a specific role for heritable defects in mitotic and telomere biology in risk of sarcomas. Citation Format: David M. Thomas. A population-based, whole genome sequencing approach to mapping the genetic basis of mesenchymal malignancies [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA030.
Abstract IA015: ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops
Authors: Kevin B. Jones
Journal: Clinical Cancer Research (2022)

Abstract Aberrant transcription in alveolar soft part sarcoma and some Xp11-rearranged renal cell carcinomas is orchestrated by the fusion oncoprotein, ASPSCR1-TFE3, expressed from a t(X;17) chromosomal translocation-mediated fusion gene. Here, proteomic analysis of proteins co-immunoprecipitated with ASPSCR1-TFE3 from human cell lines and mouse genetically-induced tumors revealed strong enrichment of a AAA+ ATPase with known segregase function. Native gel and electron microscopy found that ASPSCR1-TFE3 associates multi-valently with segregase hexamers. Forward and reverse genetic experiments with ASPSCR1-TFE3 and the segregase demonstrated that they function co-dependently for cancer cell proliferation. The presence, hexamer assembly, and enzymatic function of the segregase enabled the transcriptional impact of ASPSCR1-TFE3. The two proteins co-distributed across chromatin genome-wide, associated with enhancers, indicated by flanking H3K27ac enrichment in human cell lines, human tumors, and genetically engineered mouse tumors. These assembled into higher-order chromatin conformation structures demonstrated by HiChIP and downregulated by loss of ASPSCR1-TFE3 or the segregase. Thus, a segregase was found to assemble chromatin into three-dimensional structures as a co-factor of oncogenic transcriptional regulation. Citation Format: Kevin B. Jones. ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA015.
Abstract B026: Expression levels of chaperonin containing TCP1 in cancer are among the highest in sarcomas
Authors: Amanda J. Cox, Annette Khaled
Journal: Clinical Cancer Research (2022)

Abstract Protein folding complexes are essential for oncogenesis. Of these, the multi-subunit complex, Chaperonin-Containing TCP-1 (CCT or TRiC), is upregulated across a spectrum of cancers and folds many of the oncoproteins that drive cancer growth. Using the UCSC Xena online database, which includes datasets from TCGA, TARGET, GTEx, and KidsFirst, we found significant increases in gene expression of the subunits (CCT1-8) that form the chaperonin complex in sarcomas, both adult and pediatric, as compared to other cancers like invasive breast carcinoma, lung carcinoma, glioblastoma multiforme, or prostate cancer. Most notably was the high expression of the second subunit (CCT2) in Rhabdomyosarcoma compared to other pediatric cancers. These findings were confirmed with other databases (e.g., Oncomine). Expression of CCT subunits, like CCT2, was decreased in normal tissues, such as muscle, kidney, and uterus, as compared to sarcoma tissues. Bioinformatic data was confirmed by finding detectable staining of CCT2 protein in sarcoma tissues. This was supported by data from the human protein atlas showing minimal staining for CCT2 in normal smooth and skeletal muscle. Cancer adjacent tissues from a metastatic breast cancer patient study had minimal staining for CCT2 in muscle, fat, and bone. These data show that CCT is increased in sarcomas, while decreased in normal tissues, and has potential for further study as a driver of sarcoma development and a target for therapeutic intervention. Citation Format: Amanda J. Cox, Annette Khaled. Expression levels of chaperonin containing TCP1 in cancer are among the highest in sarcomas [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B026.
Abstract B020: Multimodal single-cell analyses reveal identification of unique transcriptional subgroups in ewing sarcoma
Authors: April A. Apfelbaum, Olivia Waltner, Shruti S. Bhise, Sami Kanaan, Jay F. Sarthy, Scott N. Furlan, Elizabeth R. Lawlor
Journal: Clinical Cancer Research (2022)

Abstract Ewing sarcoma (EwS) tumors are driven by pathognomonic fusions between FET proteins and ETS family transcription factors (most frequently EWS::FLI1). EWS::FLI1 drives tumorigenesis through massive transcriptomic and epigenomic rewiring. Despite mutational homogeneity, EwS are highly transcriptionally heterogeneous suggesting that cell context is a key determinant of EWS::FLI1-driven gene signatures. Fusion protein activity has been revealed as a core source of EwS heterogeneity. However, deep investigation into the transcriptomic and epigenomic heterogeneity of EwS cells has yet to be described. Molecular subtyping of EwS has thus far proven to be difficult to achieve with bulk RNA-sequencing approaches. We hypothesized that single-cell characterization of EwS cells would provide the necessary resolution to allow identification and characterization of transcriptionally distinct tumor subgroups. We subjected eight established EwS cell lines, one PDX-derived EwS line, and five non-EwS cell lines to single-cell multiomic (ATAC + RNA) sequencing. A range of 1300-3800 live cells were captured per sample, with an average of 25,000 transcript and accessible reads per cell. Initial analysis of transcriptomes confirmed the EwS-specific, EWS::FLI1-dependent signature gene sets in EwS samples. Integrated analysis of the multiome data from the 9 EwS samples identified inter-tumor heterogeneity and unsupervised k-means clustering revealed three molecular subgroups that were not evident from expression data alone. Subgroup 1 comprised only the A673 cell line, while the remaining 8 EwS samples were split between subgroups 2 and 3. Gene ontology analysis defined enrichment of distinct gene sets across the 3 subgroups. Interestingly, expression of subgroup 2-defining genes was reduced following knockdown of EWSR1::FLI1, while expression of subgroup 3-defining genes increased. Thus, these data show that transcriptionally distinct subgroups of EwS exist and these are defined, in part, by whether EWS::FLI1-dependent gene activation or gene repression dominates transcriptional rewiring. Our ongoing studies suggest that these molecular subgroups are defined by cooperation between the fusion and cell context-dependent transcription factors. Future analyses will determine if these distinct multiomic programs exist in primary patients tumors and test the pathobiologic and clinical significance of these novel molecular subgroups. Citation Format: April A. Apfelbaum, Olivia Waltner, Shruti S. Bhise, Sami Kanaan, Jay F. Sarthy, Scott N. Furlan, Elizabeth R. Lawlor. Multimodal single-cell analyses reveal identification of unique transcriptional subgroups in ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B020.
Abstract A006: Defining the microenvironment of alveolar soft part sarcoma &amp; it’s role in therapeutic outcomes
Authors: Alexis M. Philippot, Ngoc Ha Dang, Shyam V. Menon, Jennifer Bourdage, Xueqing Lun, Bo Young Ahn, Stephen M. Robbins, Donna L. Senger
Journal: Clinical Cancer Research (2022)

Abstract Alveolar soft part sarcoma (ASPS) is a rare pediatric malignancy which has characteristically poor clinical outcomes due to a propensity to metastasize along with a complete lack of chemotherapeutic options. One additional difficulty of this rare tumor is an absence of established in vivo models. Here, we describe the establishment of a patient derived xenograft model (PDX), and corresponding cell line, from the lung metastases of a 14-year-old female diagnosed with ASPS. Using this model, we performed a drug screen, from which the proteasome inhibitor carfilzomib inhibited tumor cell viability and growth in vitro and in vivo. To further elucidate factors implicated in tumor progression and chemotherapy resistance, we characterized the microenvironment and secretome of the ASPS PDX. In keeping with recent literature showing large numbers of tumor associated macrophage (TAMs) in ASPS, we found that 96% of the myeloid cells present in the PDX were TAMS, with 35% taking on a pro-tumor phenotype. Further, factors secreted by the tumor microenvironment largely support immune cell recruitment and pro-tumor phenotypes. Interestingly, in vivo assessment demonstrates that Iba1+ macrophage populations decrease by 60% with carfilzomib treatment. This prompted investigation into the potential impact of TAMs on ASPS growth and progression, and if they are implicated in the therapeutic response to carfilzomib. Based on preliminary findings that carfilzomib targets the pro-tumor phenotypic states of bone marrow derived macrophage in vitro, we hypothesize that carfilzomib alters the recruitment and phenotype of TAMs, decreasing tumor cell viability in vitro, and thus tumor burden in vivo. Citation Format: Alexis M. Philippot, Ngoc Ha Dang, Shyam V. Menon, Jennifer Bourdage, Xueqing Lun, Bo Young Ahn, Stephen M. Robbins, Donna L. Senger. Defining the microenvironment of alveolar soft part sarcoma &amp; it’s role in therapeutic outcomes [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr A006.
Abstract B011: Two epigenetically distinct cellular states in osteosarcoma are regulated by a cluster-specific set of pioneer transcription factors
Authors: Eunice Lopez Fuentes, Andrew Clugston, Leanne C. Sayles, E. Alejandro Sweet-Cordero
Journal: Clinical Cancer Research (2022)

Abstract The Osteosarcoma (OS) genome is characterized by aneuploidy and dramatic structural rearrangements often leading to copy number gain and loss. There is significant heterogeneity between patients. Additionally, there is less known regarding the epigenetic heterogeneity within osteosarcoma and how this may impact critical phenotypes such as therapy response and metastasis. To characterize the osteosarcoma epigenome, we integrated ATAC-seq and RNA-seq across a unique set of patient samples, PDXs and PDX-derived cell lines obtained across the disease continuum and including biopsies, resections, and metastases. Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) analysis revealed the presence of two distinct epigenetic cell states. Differential chromatin accessibility between the clusters showed ~3000 unique open regions per cluster. Using GREAT to associate the differential genomic regions to genes, the enriched pathways of Cluster 1 (C1) are related to mesenchymal cell proliferation, skeletal system morphogenesis, osteoblast differentiation, and Wnt signaling pathway, whereas Cluster 2 (C2) enriched pathways are related to cell motility and migration, extracellular matrix organization and regulation of protein serine/threonine kinase activity. Accessible regions in the chromatin were enriched for a unique set of transcription factor binding sites. C1 accessible regions are enriched with transcription factor binding motifs (TFBM) related to development including RUNX2/3, MEOX2, HOXA2/5, VAX1/2, MEF, VSX and DLX; whereas members of AP1 complex including FOSL1/2, c-FOS, JUN are TFBM enriched in open regions in C2. This is correlated with high protein expression of these transcription factors in a cluster-specific manner and differential binding to chromatin. As expected, gene expression showed a positive correlation with accessible regions in promoters. RUNX2 plays a major role in chromatin remodeling in C1, modifying the chromatin accessibility of 5300 regions, most located in &amp;lt;1kb from the promoters. In conclusion, we uncovered two epigenetically cell states regulated by a cluster-specific set of transcription factors which are able to remodel the chromatin. Citation Format: Eunice Lopez Fuentes, Andrew Clugston, Leanne C. Sayles, E. Alejandro Sweet-Cordero. Two epigenetically distinct cellular states in osteosarcoma are regulated by a cluster-specific set of pioneer transcription factors [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B011.
Reply to Leonard P. Bokhorst and Berdine L. Heesterman’s Words of Wisdom re: High-dose Radiotherapy and Risk-adapted Androgen Deprivation in Localised Prostate Cancer (DART 01/05): 10-Year Results of a Phase 3 Randomised, Controlled Trial. Eur Urol. 2022;82:441
Authors: Almudena Zapatero, Felipe A. Calvo, Carmen Gonzalez San-Segundo, Ana Alvarez
Journal: European Urology (2022)
Oral corticosteroids in asthma and beyond: moving forward
Authors: Jeffrey Shi Kai Chan, Ruth B. Murray, David Price
Journal: European Respiratory Journal (2022)

<b>While life-saving in severe exacerbations, oral corticosteroid (OCS) use in asthma is increasingly recognised as a cause of short- and long-term adverse effects; this requires implementation of OCS stewardship strategies to minimise the need for their use</b>https://bit.ly/3LDDoBd
More than meets the eye
Authors: Gerard N. Olive, Ian A. Yang, Henry Marshall, Rayleen V. Bowman, Kwun M. Fong
Journal: European Respiratory Journal (2022)

Lung cancer biology has changed, with a histological shift from the previously dominant central squamous cell carcinoma to peripheral lung adenocarcinomas. Changes in cigarette characteristics and smoking practice are commonly attributed; however, other carcinogens such as air pollution and diesel fumes may also play an as yet unidentified role in lung cancers in never-smokers [1]. This shift and advances in cross sectional imaging have resulted in increasing adoption of low dose computed tomography (CT)-based lung cancer screening, when earlier attempts with chest radiography and sputum cytology failed [2]. Autofluorescence bronchoscopy can detect proximal preneoplastic lesions. Intensive surveillance with this modality, however, may not alter health outcomes. <https://bit.ly/3s98vN1>
Deep immunophenotyping reveals biomarkers of multisystemic inflammatory syndrome in children in a Latin American cohort
Authors: Emma Rey-Jurado, Yazmin Espinosa, Camila Astudillo, Lina Jimena Cortés, Juan Hormazabal, Loreani P. Noguera, Fernanda Cofré, Cecilia Piñera, Ricardo González, Alexander Bataszew, Paula Muñoz Venturelli, Dona Benadof, Patricia Álvarez, Valeria Acevedo, Pablo Vial, Cecilia Vial, M. Cecilia Poli
Journal: Journal of Allergy and Clinical Immunology (2022)